Despite the extensive documentation on HIV-1 infectivity, replication within target cells, mechanism(s) of viral immunopathogenesis, and the development of AIDS in adults, no specific cellular- and/or molecular-based studies have been published to date examining any differential infectivity or propagation of HIV-1 within immune cells derived from elderly subjects or within HIV-1-infected elderly patients. Results from our laboratory have demonstrated significant differences in viral growth between young and aged human and primate mononuclear cells. Increased titers of virus were observed in HIV-1-infected aged mononuclear cells and lymphocytes compared to virally infected cells from younger donors. We believe that aged lymphocytes may be less susceptible to HIV-1-mediated cell death and may serve as a reservoir promoting virion production. Given T cell phenotypic alterations that have been observed in various chronic inflammatory disease states and aging, we believe that a similar systemic Th2 polarization may occur in circulating T cells of elderly subjects making them more susceptible to HIV-1 disease. Based on these findings, we are examining various parameters of HIV-1-mediated signaling, replication and immunopathogenesis using young and aged mononuclear cells and T lymphocytes. Additional studies are being performed examining alterations in the circulating homocysteine, vitamin B12, folate, and red blood cell folate levels in these subjects to determine if there are any age- and HIV-related changes in these subjects and any possible correlations with immune phenotypes and cellular apoptosis. In addition, we have continued our research studying the basic biology of the chemokine co-receptors and the various signaling molecules and raft-associated molecules required for their activity. Finally, we have identified several new and novel chemokine receptor antagonists that block several receptors and are capable of blocking HIV infectivity and binding as well as chemokine function. We believe these antagonists may have potential therapeutic value in the treatment of AIDS. Overall, these studies should provide invaluable information on age-related differences in chemokine biology and HIV-1 infectivity and pathogenesis.